Smoking contributes to a multitude of chronic diseases, including chronic obstructive lung disease (COPD) and lung cancer;approximately 15% of smokers will develop these diseases. The link between COPD and lung cancer has been demonstrated in epidemiologic studies, as well as family studies suggesting a common underlying genetic contribution to these diseases. The biologic mechanisms linking COPD and lung cancer are unknown, however chronic inflammation is likely to play a role. We propose to evaluate SNPs and copy number variation in genes in inflammatory pathways. The proposed study will expand on previous work by incorporating COPD phenotyping using CT diagnosis of emphysema and pulmonary function testing (PFT). It also will expand on the panel of genes beyond those few already evaluated, will incorporate copy number variation as well as non-synonymous and functional SNPs, and will include a large African American population. There has not been a study of these pathway genes in African Americans, a group that is less likely to report COPD, smokes fewer cigarettes, but is more likely to be diagnosed with lung cancer than whites. Specifically, from two large, urban health systems we will recruit 2050 lung cancer cases, 2050 smokers, and 600 patients with COPD. Approximately 46% of subjects will be African American. Each subject will complete a risk factor questionnaire, undergo CTs and PFTs, provide a blood sample, and when available a tissue block. It is hypothesized that genetic variation in inflammation-related genes contributes to the development of lung cancer and this association varies by the presence or absence of COPD, and by race. The goal is to develop a genetic profile based on SNPs and copy number variation in inflammation pathway genes that predicts susceptibility to lung cancer with and without COPD in response to tobacco exposure. In addition, gene expression of a panel of 370 inflammatory pathway genes will be evaluated in normal lung tissue in a subset of 250 cases with and 250 cases without a COPD diagnosis. No other large collection of cases is available that includes detailed phenotyping of lung cancer and COPD and jointly evaluates inflammatory genes in germline DNA and target tissue in the same individuals. This work will lead to a better understanding of the inflammatory process in lung carcinogenesis, provide avenues for the identification of a high risk group for intervention, and provide insight into possible treatment options. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths and COPD is the 4th leading cause of death in adults;together they account for substantial mortality and morbidity with limited treatment options. This study will elucidate new pathways on which to focus treatment efforts and identify target populations for interventions and screening.